Stem cell transplantation (SCT), with adult stem cells, is currently performed to rescue bone marrow cells destroyed by high doses of radiation or chemotherapy used to kill cancer cells. The problem is that many SCTs are unsuccessful, particularly allogeneic SCT in which matched donor stem cells are required. SCT patients can suffer from severe immunodeficiencies due to poor immune reconstitution, leading to infections, relapse of the original cancer or secondary cancers. The development of graft-versus-host disease (GVHD), in which donor lymphocytes attack the recipient's organs, also impedes recovery.
Effective agents to promote post-transplant immune reconstitution and prevent the resurgence of cancer are needed. To this end, cytokines are attractive candidates. The cytokine, Interleukin-7 (IL-7), has potent proliferative capacity. Recent phase 1 clinical trials reported that minimal toxicity was incurred with IL-7 treatment. IL-7, originally described in 1988 as a growth factor for immature B cells (Namen et al., 1988), has emerged as an important regulator of T-cell development (von Freeden-Jeffry et al., 1995) as well as for homeostasis of peripheral T-cells and maintenance of long-term memory T-cells (Schluns et al., 2000; Kieper et al., 2002).
IL-7 is a 25 kDa protein that was discovered as the product of a thymic stromal cell line (Sakata et al., 1990). IL-7 is not produced by lymphocytes and, although IL-7 mRNA has been detected in lymph nodes (Link et al., 2007), the protein itself has not been found in any secondary lymphoid organs. Circulating serum levels of IL-7 in normal individuals are very low (0.3-8.4 pg/mL) (Fry et al., 2001). Originally thought to be constitutively produced, IL-7 production by non-lymphoid cells can be induced upon infection. In response to engagement of Toll-like receptor (TLR) signaling, liver hepatocytes produced IL-7 (Sawa et al., 2009), while the presence of IFN-γ and commensal microflora promoted the production of IL-7 in the intestines (Shalapour et al., 2010). High circulating amounts of IL-7 are not naturally occurring in healthy individuals.
The receptor for IL-7 (IL-7R), expressed by lymphocytes, consists of the IL-7Rα chain and the common cytokine γ chain (γc) (Kovanen and Leonard, 2004). Upon binding of IL-7, the two receptor chains heterodimerize and initiate a series of signaling events mediated through receptor-associated kinases, JAK1/JAK3, which phosphorylate and activate STAT5 (reviewed in (Kittipatarin and Khaled, 2007)). Hence, unlike other cytokines, such as IL-2 or IL-15, where receptor binding affinity regulates activity, it is the amount of IL-7 available to engage the IL-7R that determines the strength of the IL-7 signal transduced. For this reason, over expression of IL-7, as has been achieved with IL-7 transgenic mice, results in severe immune proliferative disorders that cause lymphoma development (Rich et al., 1993; Yamanaka et al., 2006).
What is needed in the art are compositions and methods for increasing growth, survival, and immune response of cells in subjects in need thereof. What is needed are compositions and methods comprising IL-7 that provide beneficial outcomes without severe side effects from increased levels of IL-7.